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Iron in skin of mice with three etiologies of systemic iron overload.

ABSTRACT: In human hemochromatosis, tissue toxicity is a function of tissue iron levels. Despite reports of skin toxicity in hemochromatosis, little is known about iron levels in skin of individuals with systemic iron overload. We measured skin iron and studied skin histology in three mouse models of systemic iron overload: mice with a deletion of the hemochromatosis (Hfe) gene, mice fed a high iron diet, and mice given parenteral injections of iron. In Hfe(-/-) mice, iron content in the epidermis and dermis was unexpectedly the same as in Hfe(+/+) mice, and there were no histological abnormalities detected after 30 wk. A high iron diet produced increased iron in the epidermis of both normal and Hfe(-/-) animals; a high diet increased iron in the dermis only in Hfe(-/-) mice. Increased skin iron was not associated with other histological changes, even after 19 wk. Parenteral administration of iron produced increased iron in the epidermis and dermis, and gave the skin a bronze hue. These results show that the amount and distribution of iron in the skin depends on the etiology of iron overload. It appears that neither Hfe deletion nor elevated skin iron alone can account for cutaneous manifestations reportedly seen in humans with hereditary hemochromatosis.

SUBMITTER: Adams BD

PROVIDER: S-EPMC2243217 | biostudies-literature | 2005 Dec

REPOSITORIES: biostudies-literature

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Iron in skin of mice with three etiologies of systemic iron overload.

Adams Brian D BD Lazova Rossitza R Andrews Nancy C NC Milstone Leonard M LM

The Journal of investigative dermatology 20051201 6

In human hemochromatosis, tissue toxicity is a function of tissue iron levels. Despite reports of skin toxicity in hemochromatosis, little is known about iron levels in skin of individuals with systemic iron overload. We measured skin iron and studied skin histology in three mouse models of systemic iron overload: mice with a deletion of the hemochromatosis (Hfe) gene, mice fed a high iron diet, and mice given parenteral injections of iron. In Hfe(-/-) mice, iron content in the epidermis and der ...[more]

PMID: 16354190

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Project description:Systemic iron levels must be maintained in physiological concentrations to prevent diseases associated with iron deficiency or iron overload. A key role in this process plays ferroportin, the only known mammalian transmembrane iron exporter, which releases iron from duodenal enterocytes, hepatocytes, or iron-recycling macrophages into the blood stream. Ferroportin expression is tightly controlled by transcriptional and post-transcriptional mechanisms in response to hypoxia, iron deficiency, heme iron and inflammatory cues by cell-autonomous and systemic mechanisms. At the systemic level, the iron-regulatory hormone hepcidin is released from the liver in response to these cues, binds to ferroportin and triggers its degradation. The relative importance of individual ferroportin control mechanisms and their interplay at the systemic level is incompletely understood. Here, we built a mathematical model of systemic iron regulation. It incorporates the dynamics of organ iron pools as well as regulation by the hepcidin/ferroportin system. We calibrated and validated the model with time-resolved measurements of iron responses in mice challenged with dietary iron overload and/or inflammation. The model demonstrates that inflammation mainly reduces the amount of iron in the blood stream by reducing intracellular ferroportin transcription, and not by hepcidin-dependent ferroportin protein destabilization. In contrast, ferroportin regulation by hepcidin is the predominant mechanism of iron homeostasis in response to changing iron diets for a big range of dietary iron contents. The model further reveals that additional homeostasis mechanisms must be taken into account at very high dietary iron levels, including the saturation of intestinal uptake of nutritional iron and the uptake of circulating, non-transferrin-bound iron, into liver. Taken together, our model quantitatively describes systemic iron metabolism and generated experimentally testable predictions for additional ferroportin-independent homeostasis mechanisms.

Dataset Information

Iron in skin of mice with three etiologies of systemic iron overload.

Publications

Iron in skin of mice with three etiologies of systemic iron overload.

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